Abstract
Inhibition of oxidative metabolism is often found to decrease contractility of systemic vascular smooth muscle, but not to reduce global [Ca(2+)](i). In the present study, we probe the hypothesis that it is associated with an altered pattern of intracellular Ca(2+) oscillations (waves) influencing force development. In the rat tail artery, mitochondrial inhibitors (rotenone, antimycin A, and cyanide) reduced alpha(1)-adrenoceptor-stimulated force by 50% to 80%, but did not reduce global [Ca(2+)](i). Less relaxation (about 30%) was observed after inhibition of myosin phosphatase activity with calyculin A, suggesting that part of the metabolic sensitivity involves the regulation of myosin 20-kDa light chain phosphorylation, although no decrease in phosphorylation was found in freeze-clamped tissue. Confocal imaging revealed that the mitochondrial inhibitors increased the frequency but reduced the amplitude of asynchronous cellular Ca(2+) waves elicited by alpha(1) stimulation. The altered wave pattern, in association with increased basal [Ca(2+)](i), accounted for the unchanged global [Ca(2+)](i). Inhibition of glycolytic ATP production by arsenate caused similar effects on Ca(2+) waves and global [Ca(2+)](i), developing gradually in parallel with decreased contractility. Inhibition of wave activity by the InsP(3) receptor antagonist 2-APB correlated closely with relaxation. Furthermore, abolition of waves with thapsigargin in the presence of verapamil reduced force by about 50%, despite unaltered global [Ca(2+)](i), suggesting that contraction may at least partly depend on Ca(2+) wave activity. This study therefore indicates that mitochondrial inhibition influences Ca(2+) wave activity, possibly due to a close spatial relationship of mitochondria and the sarcoplasmic reticulum and that this contributes to metabolic vascular relaxation.
Original language | English |
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Pages (from-to) | 792-799 |
Journal | Circulation Research |
Volume | 90 |
Issue number | 7 |
DOIs | |
Publication status | Published - 2002 |
Subject classification (UKÄ)
- Cardiac and Cardiovascular Systems
Free keywords
- Calcium Signaling : drug effects
- Calcium : metabolism
- Cyanides : pharmacology
- Calcium Signaling : physiology
- Enzyme Inhibitors : pharmacology
- Female
- Intracellular Fluid : metabolism
- In Vitro
- Glycolysis : drug effects
- Isometric Contraction : drug effects
- Mitochondria : drug effects
- Mitochondria : metabolism
- Myosin Light Chains : metabolism
- Phosphorylation : drug effects
- Rats
- Sprague-Dawley
- Receptors
- alpha-1 : metabolism
- Adrenergic
- Rotenone : pharmacology
- Support
- Tail : blood supply
- Non-U.S. Gov't
- Vasoconstriction : drug effects
- Arteries : metabolism
- Arteries : drug effects
- Arsenates : pharmacology
- Antimycin A : pharmacology
- Macrolide : pharmacology
- Antibiotics
- Animal
- Adrenergic alpha-Agonists : pharmacology
- Uncoupling Agents : pharmacology